Vocal communication is an essential part of human social behavior. Age-related hearing loss, presbycusis, is one of the most common communication disorders and hearing deficits. One treatment that has been shown to reduce age-related hearing loss, especially at higher frequencies, is estrogen therapy. The molecular and physiological mode of estrogen action on the auditory system is unknown. Because of the health risks of estrogen therapy, including breast cancer and cardiovascular disease, it is important to develop therapies that target the auditory system and produce the beneficial effects of estrogen without the risks. The midshipman fish is an excellent model for the study of estrogen actions on the auditory system as the animal has been shown to exhibit estrogen-dependent auditory plasticity in the inner ear which promotes high frequency hearing in these animals. This application will investigate the role of large conductance calcium-activated potassium (BK) channels in the peripheral auditory system of these animals. BK channels play critical roles in hearing in mammal and non-mammalian vertebrates and the alternative splicing of the gene encoding these channels is regulated by steroid hormones, including estrogen, in these systems. Using in vivo physiology and quantitative real-time PCR this application aims to determine whether BK currents change in an estrogen-dependent manner and whether the expression of the gene encoding these channels contributes to such auditory plasticity. A comparison between BK channels produced from the novel two Slo1 genes in the midshipman and the single mammalian gene will identify new functional domains that may serve as targets for pharmaceutical treatment of human diseases associated with BK channels such as epilepsy. In vitro studies will then determine whether the kinetic properties of midshipman BK channels can account for the frequency encoding properties of the auditory system of these animals. In humans it has been shown that estrogen treatment protects the loss of high frequency hearing that occurs during aging. Understanding how estrogen acts to enhance high frequency hearing in the midshipman fish will identify a potential mechanism for estrogen action on the human auditory system. Comparing ion channel properties between fish and mammals aims to identify new functional domains to target for treatment of diseases such as epilepsy caused by malfunctions in such ion channels.